Background: 16p11.2 breakpoint 4 to 5 copy number variants (CNVs) increase the risk for developing autism spectrum disorder, schizophrenia, and language and cognitive impairment. In this multisite study, we aimed to quantify the effect of 16p11.2 CNVs on brain structure. Methods: Using voxel- and surface-based brain morphometric methods, we analyzed structural magnetic resonance imaging collected at seven sites from 78 individuals with a deletion, 71 individuals with a duplication, and 212 individuals without a CNV. Results: Beyond the 16p11.2-related mirror effect on global brain morphometry, we observe regional mirror differences in the insula (deletion > control > duplication). Other regions are preferentially affected by either the deletion or the duplication: the calcarine cortex and transverse temporal gyrus (deletion > control; Cohen's d > 1), the superior and middle temporal gyri (deletion < control; Cohen's d < −1), and the caudate and hippocampus (control > duplication; −0.5 > Cohen's d > −1). Measures of cognition, language, and social responsiveness and the presence of psychiatric diagnoses do not influence these results. Conclusions: The global and regional effects on brain morphometry due to 16p11.2 CNVs generalize across site, computational method, age, and sex. Effect sizes on neuroimaging and cognitive traits are comparable. Findings partially overlap with results of meta-analyses performed across psychiatric disorders. However, the lack of correlation between morphometric and clinical measures suggests that CNV-associated brain changes contribute to clinical manifestations but require additional factors for the development of the disorder. These findings highlight the power of genetic risk factors as a complement to studying groups defined by behavioral criteria.
Bibliographical noteFunding Information:
This work was supported by Simons Foundation Grant Nos. SFARI219193 (to RLB) and SFARI274424 (to AR); a Bursary Professor fellowship of the Swiss National Science Foundation (SNSF) (to SJ); SNSF Grant No. 31003A160203 (to AR); SNSF Sinergia Grant No. CRSII33-133044 (to AR); SNSF National Centre of Competence in Research Synapsy and project Grant No. 32003B_159780 (to BD); Foundation Parkinson Switzerland and Foundation Synapsis (to BD); European Union Seventh Framework Programme (FP7/2015-2018) Grant No. 604102 (Human Brain Project) (to BD); the Roger De Spoelberch and Partridge Foundations; a Canada Research Chair in neurodevelopmental disorders (to SJ), and a chair from the Jeanne et Jean Louis Levesque Foundation (to SJ). This research was enabled by support provided by Calcul Quebec ( http://www.calculquebec.ca ) and Compute Canada ( http://www.computecanada.ca ).
We thank all of the families at the participating Simons Variation in Individuals Project (VIP) sites, as well as the Simons VIP Consortium. We appreciate obtaining access to imaging and phenotypic data on SFARI Base. Approved researchers can obtain the Simons VIP population dataset described in this study by applying at https://base.sfari.org . Statistical support was provided by data scientist Steven Worthington, at the Institute for Quantitative Social Science, Harvard University. We are grateful to all families who participated in the 16p11.2 European Consortium.
- Autism spectrum disorder
- Copy number variant
- Neurodevelopmental disorders